Project Description

Abstract

Metastasis causes up to 90% of deaths related to the presence of tumors. Recent studies have shown that metastasis can be initiated by over-expression of a fatty acid receptor (CD36). Also, it has been shown that metastasis development depends directly on long chain fatty acid (LCFA) dietary uptake, particularly palmitic acid (PA). Since most foods contain LCFA, it would be unfeasible its avoidance by dietary restriction, therefore developing a system capable of reducing its intestinal absorption could be a new approach to tackle metastasis. We plan to use synthetic biology to design a probiotic with increased fatty acid uptake and with PA specificity. By decreasing PA concentration in the intestinal lumen and consequently its absorption and blood levels, we expect preventing it from being used as an energy source for metastatic cells.

Introduction

Metastasis occurs when a cancer spreads from the original tumor to other parts of the body. Currently, controlling metastasis is still a challenge and causes up to 90% of deaths related to the presence of tumors (Mehlen & Puisieux, 2006). It has recently been shown that a fat component, called palmitic acid, can cause metastasis in tumor cells (Pascual et al., 2017). A main problem here is that palmitic acid is found in many foods so dietary restriction is not possible.

On the other hand, in our gut we find millions of bacteria, which are known as the intestinal microbiota (Gerritsen, Smidt, Rijkers, & de Vos, 2011). These bacteria perform many beneficial functions. We had the following idea: What if we could develop a gut microorganism, capable of up taking palmitic acid and acting as a fatty acid sponge? Achieving so would provide us with a potential mechanism for combating metastasis, and it could also be applied to treat other metabolic diseases.

The study, which is the central idea of our project, has described that cancer cells expressing high levels CD36 receptor, a long chain fatty acid scavenger receptor, are more likely to initiate metastasis in the presence of an excess of dietary fat. Hence, overexpression of CD36 in cell lines increased their potential to metastasize. Besides, this study also showed that the presence of CD36+ metastasis-initiating cells correlates clinically with a poor prognosis.

With these recent findings, a CD36-based anti-metastatic therapy has been proposed, in which the use of anti-CD36 neutralizing antibodies would block fatty acid intake in cancer cells and thus its ability to develop metastasis.

In an attempt to propose an alternative approach to the already existing antibody, our project intents to benefit from the presence of bacteria in our intestines. Thus, we aim to design a probiotic with an enhanced metabolism able to increase fatty acid absorption. Our goal is to reduce palmitic acid intestinal absorption, since its presence in most foods makes unfeasible its avoidance by dietary restriction. By doing so we could halt tumor cells from becoming metastatic.

We believe that our probiotic would serve as a complementary approach, with low cost and accessible in places where an infrastructure for administration of antibodies is not yet available. Once we develop our system, we plant to further optimize it for the use in the treatment of other metabolic diseases.

• Aim 1: Design a proof of concept of a probiotic with enhanced FA uptake using the following strategies:
• Overexpression of bacterial endogenous proteins related with FA absorption.
• Directed evolution for increasing the efficiency of the system (multiplex automated genome engineering and other strategies).
• Nature inspired design: explore and reproduce mechanisms that are used in bacteria that live in a high FA environment.
• Engineer bacterial response mechanisms to environmental fatty acid energy sources.
• Aim 2: Demonstrate that our system efficiently prevents metastasis in-vitro by removing palmitic acid from growth media. Our strategy is to co-culture them with tumor cells.
• Aim 3: Plan a study based on the administration of our probiotic in rodent models.
• Aim 4: Develop a strategy to explore how we can expand the use of our fatty acid sponge to treat other metabolic diseases and broader applications of our probiotic.

References

Gerritsen, J., Smidt, H., Rijkers, G. T., & de Vos, W. M. (2011). Intestinal microbiota in human health and disease: the impact of probiotics. Genes & nutrition.

Mehlen, P., & Puisieux, A. (2006). Metastasis: A question of life or death. Nature Reviews Cancer.

Pascual, G., Avgustinova, A., Mejetta, S., Martín, M., Castellanos, A., Attolini, C. S. O., Berenguer, A., et al. (2017). Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature.

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